tbuckley/cabot-search huggingface dataset:
Characterizing immune-genomic signatures associated with response to immune checkpoint inhibitors (ICI) in patients with metastatic urothelial carcinoma (mUC).
Authors: Nikhil Pramod, Scott Dawsey, Paul G. Pavicic, Roshan Lodha, Ubenthira Patgunarajah, Monica Nair, Moshe Chaim Ornstein, Timothy D. Gilligan, Christopher Eing Wee, Omar Y. Mian, Amanda Nizam, Jane Nguyen, C. Marcela Diaz-Montero, Shilpa Gupta
Journal: Journal of Clinical Oncology (2023)

e16582 Background: Response rates with ICI are modest at around 20% in mUC and there is a lack of validated biomarkers to select pts who are likely to derive benefit from ICI. There is an unmet need to develop biomarkers of response and resistance to avoid unnecessary treatment (Tx) and spare physical and financial toxicity. Here we report tumor immune-genomic characteristics associated with response and resistance to ICI in mUC. Methods: We selected 58 mUC pts who received at least 2 cycles of ICI (atezolizumab or pembrolizumab) between 2015-2020 and had pre-Tx archival formalin fixed paraffin-embedded (FFPE) tissues available. Pts were categorized by their response to ICI as responders (R) (Complete Response (CR), Partial Response (PR), and Stable Disease (SD)) (N = 30) or non-responders (NR) (Progressive Disease (PD)) (N = 28). Tumor was macrodissected from FFPE slides and RNA extraction was done using Qiagen Rneasy FFPE kit. 100ng of RNA was used for transcriptomic analysis using the Nanostring PanCancer IO 360 panel. Data normalization and analysis was carried out using nSolver 4.0. Results: Differential expression analysis comparing (R) vs (NR) displayed upregulation of gene signatures associated with Immunoproteasome, Antigen presenting machinery (APM), IFN Gamma, PD-L1, and IFN downstream. Additionally, the tumor inflammation signature (TIS), which is trained to predict response to ICI, was upregulated in (R) vs (NR) (Table 1). Single gene analysis showed trend towards upregulation of ISG15 (logFC = 0.7821, p = 0.00337), TAP1(logFC = 0.7649, p = 0.00422), and STAT1 (logFC = 0.6053, p = 0.00510) in (R), P-values, were above significance threshold after adjustment for multiple comparisons. Receiver operator characteristic (ROC) analysis with area-under the curve (AUC) scores assess capacity of gene signatures to predict response to ICI (Table 1). In our cohort, the median overall survival for (R) was 44.1 months compared to 24.5 months in NR (p = 0.0100). Conclusions: In our cohort of mUC pts treated with ICI, we found an association between signatures of tumor immunogenicity (APM and Immunoproteosome) and anti-tumor immune activity (IFN Gamma, IFN Downstream, TIS) in pre-Tx tissue with favorable response to therapy (including SD). These findings are hypothesis generating and need to be further validated in prospective trials. Ongoing genomic and immunologic correlative studies in our cohort will further help understand comprehensive biomarkers of response and resistance to ICI in pts with mUC. [Table: see text]
Uncovering mechanisms of response of pembrolizumab and lenvatinib for the treatment of platinum-resistant high grade serous ovarian cancer.
Authors: Jeffrey How, Shannon Neville Westin, Travis T. Sims, Kathryn Lito, Joseph Celestino, Kelly M. Rangel, Weiyi Peng, Linghua Wang, Amir A. Jazaeri
Journal: Journal of Clinical Oncology (2023)

TPS5619 Background: Despite initial response to conventional platinum-containing therapies, the majority of high grade serous ovarian cancer (HGSOC) patients will eventually develop treatment resistance. Despite interest for immune checkpoint inhibitor alternatives, pembrolizumab monotherapy is poor with objective response rates (ORR) ranging between 4.1 - 10%. Poor response may be linked to higher expression of immunosuppressive factors (e.g. VEGF, TGF-β) in the tumor microenvironment (TME). In an immunosuppressive TME, monotherapy with PD-1 inhibitors can induce T-cell dysfunction and apoptosis, leading to innate resistance to pembrolizumab. Preclinical studies of other tumors have demonstrated that lenvatinib can improve T-cell activation and reduce the tumor-associated macrophage population and TGF-β/VEGF/FGF-signaling. In HGSOC, mechanisms of resistance to pembrolizumab and whether this resistance can be overcome by the addition of lenvatinib remain unknown. The objective of this investigation is to uncover the immunologic basis and synergistic mechanisms of action underlying clinical efficacy of pembrolizumab and lenvatinib in HGSOC. Specifically, we will evaluate the dynamic changes in proliferative and dysfunctional T-cell populations in the peritoneal TME (p-TME) of HGSOC patients receiving monotherapy with pembrolizumab or lenvatinib followed by combination therapy. Methods: All patients will receive a cycle of monotherapy (pembrolizumab 200 mg IV every 3 weeks or lenvatinib 20 mg po daily) followed by combination therapy (both) up to 35 cycles. Enrolled patients will receive intra-peritoneal port placement for serial peritoneal fluid evaluations (cycle 0 day 1, cycle 0 day 8, cycle 1 day 8, cycle 2 day 1, cycle 3 day 1, cycle 5 day 1, then day 1 of every 3rd cycle) for multichannel flow cytometry and single-cell RNA sequencing. Our primary translational objective is to estimate both the individual and combined effects of pembrolizumab and lenvatinib on T-cell dysfunction (PD1+ CD38+) and proliferation (ki67+) in the p-TME using multichannel flow cytometry on the peritoneal fluid. Secondary clinical objective is ORR. Secondary translational objectives include individual and synergistic effects of monotherapy and combination therapy on T-cell effector function, T-cell memory, and myeloid cell subpopulations. Exploratory objectives include evaluating the dynamic changes in immune and non-immune cells in the p-TME for exceptional responders and non-responders using single cell RNA sequencing. Key eligibility criteria include 1) histologic diagnosis of high grade serous ovarian, peritoneal, or fallopian tube cancer 2) platinum-resistant disease and 3) no prior lenvatinib therapy. The trial is open with 10 patients enrolled at the time of submission. Clinical trial information: NCT05114421 .
Biomarker-driven prospective clinical trial in renal cell carcinoma: Developing machine learning models to allocate patients to treatment arms using RNA sequencing.
Authors: Anupama Reddy, Scott Mattox Haake, Katy Beckermann, Alex Nesta, Adnan Derti, Wendy Kimryn Rathmell, Nanguneri Nirmala, Brian I. Rini
Journal: Journal of Clinical Oncology (2023)

4525 Background: RNA sequencing has shown promise in defining the biology of individual renal cell carcinoma (RCC) tumors. However, these biomarkers have not yet been translated to the clinic for prospectively assigning optimal treatments to patients. Challenges for RNA-seq biomarker development include translating classifiers across different assays/platforms, normalization of data collected from single patients in the clinic and establishing robust thresholds for assigning prediction groups. We have designed the prospective phase II OPTIC RCC clinical trial (clinicaltrials.gov NCT05361720) to test the utility of an RNA-seq based biomarker in predicting treatment based on biologic drivers relevant to angiogenesis (anti-angiogenesis; TKI) and immune microenvironment (immunotherapy; IO). Here, we will describe the development and optimization of a machine learning model for assigning individual patients to biologically driven clusters in real time to facilitate RNA-seq based biomarker trials. Methods: We have utilized RNA-seq data from the IMmotion 151 trial (ref) to develop a machine learning model. Clusters were grouped into three based on their association to tumor biology and treatment: (1) Cluster 1+2 (angiogenic signature → TKI+IO therapy), (2) Cluster 4+5 (immune/proliferative signature → dual IO therapy), (3) Cluster 3+6 (neither signature → exclude). Random forest classifier was used to train a multi-class model to predict the three groups. The model is evaluated using bootstrapped cross-validation. Results: Our machine learning classifier was built using 188 genes and has a cross-validation accuracy of 85% and sensitivity of &gt;90% in predicting patients into one of the three biological clusters from our training data. Predictions of the classifier are significantly associated with progression-free survival across different treatments within each of the predicted groups. We also observed significant odds ratios when comparing responders (CR/PR/SD) to non-responders (PD) across the treatment groups. The model was then validated in two independent test sets treated with Angio and IO inhibitors: (1) 61 patient renal cell carcinoma cohort (2) 12 patient clear cell renal cell carcinoma cohort. We observed a significant enrichment of responders to Angio+IO treatment for the predicted Cluster_Angio patients compared to IO treatment (p=0.05), highlighting the importance of matching patients to their optimal treatment. Conclusions: We have developed an accurate machine learning model to assign individual patients to RNA-seq clusters in real time. This classifier will facilitate the prospective OPTIC RCC trial. If successful, our biomarker strategy will serve as a proof of concept for selecting optimal treatments for RCC patients.
Crossing the US-Mexico border for cancer care: Which treatments are more sought-after?
Authors: Haydee Cristina Verduzco-Aguirre, Fernando Cristobal Diaz, Michael Brian LaPelusa, Fernando Aldaco, Enrique Soto Pérez de Celis
Journal: Journal of Clinical Oncology (2023)

e18576 Background: Crossing the US-Mexico border to seek healthcare is common, but limited data is available regarding cross-border cancer care. Since access and availability differs between Mexico and the US, we investigated which therapies were sought by Mexico and US-based patients crossing the border to receive cancer care. Methods: An online survey was sent to oncologists in Mexican border states (Baja California, Chihuahua, Coahuila, Nuevo León, Sonora, and Tamaulipas) using the Mexican Society of Oncology’s member directory. The survey was administered via REDCap in October-November 2022. Responses were analyzed using descriptive statistics. The study was approved by the IRB of Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Results: Sixty-six respondents completed the survey (response rate 29.3%). Most were medical (n = 24, 36.4%) or surgical (n = 24, 36.4%) oncologists practicing in both public and private settings (71.2%), with almost a third practicing in Baja California (31.8%). Sixty respondents (90.9%) reported treating US patients seeking a second opinion in Mexico. Respondents reported patients traveled to receive various treatment modalities with curative surgery (64.4%) being the most common. Seven respondents (11.9%) had interacted with patients who traveled to Mexico seeking non-FDA approved therapies, including homeopathic/alternative treatments. Thirty-one respondents (47.0%) reported treating patients traveling to buy medications with oral chemotherapy (CT) (76.7%) being the most common. Fifty respondents (75.8%) reported treating Mexican patients who traveled to the US seeking a second opinion. Respondents reported patients traveled to receive immunotherapy (59.2%). Five respondents (10.2%) treated patients who traveled to the US to receive CAR-T cell therapy, not currently available in Mexico. Twenty respondents (30.8%) reported treating patients who traveled to buy medications, with oral CT (60%) being the most common. Conclusions: Mexican oncologists often treat patients seeking cross-border cancer care. Therapies sought by patients from both sides of the border differ, mostly due to local availability. Factors associated with these differences require further study to address disparities on health outcomes across the US-Mexico border. [Table: see text]
Identification of biomarkers for early progression in muscle invasive bladder cancer (MIBC) using real-world data.
Authors: Neeraj Singh, Rohini George, Smita Agrawal
Journal: Journal of Clinical Oncology (2023)

e16568 Background: MIBC accounts for ~25% of all newly diagnosed bladder cancers and is associated with a high rate of recurrence despite radical treatment. The time to progression (TTP) can vary significantly between patients and can affect their prognosis. We leveraged a real world clinico-genomics database to classify patients as early vs late progressors, understand its impact on their outcomes and identify genetic drivers of early progression. Methods: This retrospective study was executed using the deeply curated ConcertAI Genome360 bladder cancer dataset. Only patients with confirmed MIBC status with reported tumor progression after initial treatment were considered. Based on the distribution of TTP from MIBC diagnosis of this patient cohort, we subdivided the patients into early vs late progressors. Overall survival (OS) and progression free survival (PFS) analyses were performed between these 2 cohorts. The underlying deleterious genomic mutations were identified in each cohort and differential genomic enrichment analysis was performed to identify statistically significant biomarkers correlated with early progression (p-value &lt; = 0.05). Additionally, identified biomarkers were analyzed in the context of administered therapies. Results: The TTP exhibited a bimodal distribution with a break at around 500 days, so we chose this as the cut-off to define early (N = 203) vs late progressors (N = 51). As expected, there was a significant difference in the median PFS of early vs late progressors (0.62 vs 2.41 years (p &lt; 1e-6)). The OS was also significantly different (1.98 vs 4.36 years (p = 6e-6)). We further identified mutations in 6 biomarkers which were enriched in early vs late progressors. These were CDK12 (p = 0.05), EGFR (p = 0.034), LRP1B (p = 0.05), MET (p = 0.045), PTEN (p = 0.026) and SMAD4 (p = 0.047). These patients were primarily treated with platinum-based therapies +/- gemcitabine/PD-L1 therapies in-line with MIBC treatment guidelines. The identified driver genes activate PI3K-AKT-MTOR, JAK-STAT3, b-catenin and ERK pathways which are known to interfere with the mechanism of action of platinum-based therapies, thus potentially forming the basis of early progression. Conclusions: Using our Genome360 bladder dataset, we have identified prognostic biomarkers for early progression in MIBC. This may provide clinicians with a tool to identify and modify treatment for a subset of MIBC patients who are at risk of early progression on standard of care therapies.
Multi-hospital retrospective study comparing gastric adenocarcinoma in Hispanic versus non-Hispanic patients.
Authors: Erfan Zarrinkhoo, Kyle D. Klingbeil, Shreya Condamoor, Joon Park, Nicholas Jackson, Victor Chiu, Brian E. Kadera
Journal: Journal of Clinical Oncology (2023)

e16027 Background: Gastric cancer is one of the most prevalent malignancies in the United States and carries a particularly high rate of mortality. In the United States, the overall gastric cancer rate continues to decline amongst Caucasian and African American patients; however, it remains static amongst Hispanic patients. While numerous studies have been conducted to better understand the underlying causes leading to the disproportionate incidence of gastric cancer among Hispanics, it is still not well understood. This retrospective study sought to compare the clinicopathological features and overall survival of Hispanic patients with gastric adenocarcinoma with non-Hispanic patients treated in three safety-net county hospitals in Southern California. Methods: This is a retrospective cohort study of 123 patients with newly diagnosed gastric adenocarcinoma who were treated at three safety-net county hospitals in Southern California between 2010 and 2022. The subjects were categorized as Hispanic and non-Hispanic. Clinical, pathological, and survival data were obtained from the patient chart and compared. Results: Of the 123 patients included in the study, 87 (71%) were Hispanic. At time of diagnosis, Hispanic patients were found to be significantly younger than non-Hispanics (55.4 +/- 13.5 vs 60.8 +/- 12.2, p-value 0.03). They were also more likely to be misdiagnosed (defined as greater than one prior encounter of misdiagnosis within six months) relative to non-Hispanics (26% vs 14%, p-value 0.007) despite no differences in insurance/PCP status. Hispanic patients were more likely to present with metastatic disease (65% vs 30%, p-value &lt;0.001), and were found to have a higher rate of peritoneal carcinomatosis (30% vs 8%, p-value 0.01). Hispanics were also more likely to present with disease in the gastric antrum (47% vs 19%, p-value 0.004) and have a higher rate of diffuse subtype histology (32% vs 22%, p-value 0.05). Similar rates of Helicobacter pylori infection were found within the tissue biopsy sample using Warthin Starry stain amongst Hispanic and non-Hispanic patients (17% vs 17%). Lastly, the mortality rate was higher in Hispanics relative to non-Hispanics at time of last contact (65% vs 35%, p-value &lt;0.001). Conclusions: Upon comparing clinicopathological features and mortality among gastric cancer patients who were treated in multiple safety net county hospitals, there were significant differences noticed in Hispanic American patients. Relative to non-Hispanics, Hispanic patients were more likely to be misdiagnosed, more likely to present with metastatic disease, and have higher rates of mortality despite no disparities in insurance and PCP status. Further investigation is warranted regarding possible risk factors including exposures to possible environmental triggers or if there is a genetic predisposition in Hispanic populations.
Prognosis-related molecular subtyping of nasopharyngeal carcinoma.
Authors: Qin Ding, Xiaochuan Chen, Sufang Qiu
Journal: Journal of Clinical Oncology (2023)

e18047 Background: Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic cancer, with diverse molecular characteristics and clinical outcomes. This study aims to dissect the molecular heterogeneity of NPC, followed by the construction of a mRNA -based prognostic model for prediction of treatment efficacy. Methods: We retrospectively collected a total of 193 NPC tissue samples from 2016 to 2018 for mRNA sequencing. Consensus clustering was performed to identify new molecular subgroups based on the ssgsea algorithm. Then, weighted gene co-expression network analysis (WGCNA) was used to recognize molecular subtype-associated hub genes. Finally, Cox regression analysis was applied to constructing a prognostic model for predicting risk of recurrence and metastasis. Results: Three NPC subtypes (immune, proliferation and metabolism) were identified that are molecularly distinct and clinically relevant, of which proliferation subtype is associated with poor prognosis. Immune subtype characterized by higher expression of immune checkpoint, immune cells infiltration and immunesore. Interestingly, compared with other cells, tumor cells in TME exhibited the most active metabolism pathway in single-cell sequencing analyses. The Cox regression model built on hub genes showed a close correlation with outcome (AUC = 0.81). We further validated the results using the GEO database. Conclusions: Based on biological characteristics, NPC can be novelly stratified into three subtypes. Our study identified and validated a promising prognostic model associated with molecular subtype, which may accurately anticipate the survival of NPC patients.
Immunotherapy for localized MSI-H colorectal cancer: Characterizing endoscopic and imaging response.
Authors: Daniel Aaron Fox, Tsuyoshi Konishi, Harmeet Kaur, Y. Nancy You, Kanwal Pratap Singh Raghav, Phillip S. Ge, Craig Messick, Benny Johnson, Van K. Morris, Jane V Thomas, Preksha Shah, Brian K. Bednarski, Scott Kopetz, George J. Chang, Kaysia Ludford, Victoria Higbie, Michael J. Overman, Deepak Bhamidipati
Journal: Journal of Clinical Oncology (2023)

3610 Background: Early data suggests that immunotherapy (IO) for localized colorectal cancer (CRC) is associated with high rates of pathologic complete response (pCR) and durable remission. This study aims to characterize endoscopic, imaging, and pathological outcomes among patients who received IO for localized CRC. Methods: This was a single-institution retrospective analysis of patients with MSI-H CRC who received at least one cycle of anti-PD-1 therapy for localized (stage I-III) MSI-H CRC. Patient and tumor characteristics were obtained from the clinical record. Endoscopy reports were assessed using standardized criteria to determine response and imaging was assessed using RECIST v1.1 where applicable. Endoscopic complete response (endoCR) was characterized by flat, white scar and/or telangiectasia without residual ulcer or nodularity. Categorical variables were compared using Fisher’s exact test. Results: 37 patients who received a median of 8 cycles of pembrolizumab (n = 36) or nivolumab (n = 1) for localized CRC were identified, of which 16 (43%) had a rectal primary. 10 patients (27%) had mucinous features on pathology. The best endoscopic response was complete response (CR) in 13 of 30 (43%) patients, which was achieved after a median of 6 cycles. The rate of endoCR after ≤ 4 cycles of IO was similar to the rate of endoCR after &gt; 4 cycles (29% vs 50%, p = 0.284). The best imaging response was CR in 6 of 32 (19%) of patients. The rate of CR on imaging after ≤ 4 cycles and &gt; 4 cycles of IO was 6% and 36% respectively (p = 0.064). In cases where imaging and endoscopy were available (n = 24), discrepancy in best response was noted in 14 (58%) cases. The most common discrepancy was partial response on imaging when endoCR was noted (n = 6 cases). 16 patients proceeded to surgical resection (after a median of 8 cycles) of which 11 (69%) had pCR despite non-CR on either endoscopy (n = 7) or imaging (n = 9). The endoscopic reports indicating residual disease prior to surgery included findings such as ulceration, scarring, strictures, and an obstructing mass. Of 15 patients who did not proceed to surgery and had follow-up more than 6 months after completion of IO, 13 (87%) had no evidence of progression at a median follow-up of 19.3 months from IO start. Conclusions: Discrepancies between endoscopic, imaging, and pathological outcomes were frequent, indicating a need for improved clinical response criteria. Nevertheless, immunotherapy was associated with deep and durable responses in most patients with localized MSI-H CRC.